Study of a Novel Cyanobacterial Clock Interactor KidA and the Effect of Rhythmic Glucose on Beta Cells

Earth's daily rotation creates a cyclic solar environment to which every living thing is subjected. Naturally, organisms in all kingdoms of life have evolved ways to govern their physiology according to the predictable daily changes of the environment. The external daily rhythms and internal physiological rhythms are coordinated by circadian clocks, biochemical oscillators with 24-hour periods. Circadian clocks regulate numerous pathways that are important for the survival of organisms such that their disruption can lead to fitness defects. The aim of my research was to expand our understanding of the connection of the circadian clock to the physiological processes that it regulates. In Chapter 2, I report our discovery of KidA, a novel interactor of the well-studied cyanobacterial circadian clock, which has an unexpected ability to tune the period of the clock. We unveil molecular details of the KidA-clock interaction and the period-tuning using in vivo, in vitro, and in silico methods. Containing multiple PAS domains, KidA has the potential to serve as an integrator of multiple environmental signals including the time-of-day information, motivating further research investigating its broader roles in the cell. Chapter 3 discusses my exploration of how glucose rhythms affect pancreatic beta cells, which perform important roles in glucose homeostasis through clock-regulated mechanisms. Prolonged exposure to consistently high concentration of glucose has a detrimental effect on beta cell function and survival and is linked to Type 2 Diabetes. The preliminary in vitro results from beta-TC-6 cells suggest that such glucotoxicity experienced by beta cells can be alleviated by cycling high glucose and low glucose treatments in a circadian manner, similar to the time-restricted feeding approach.